NRG-DT001 phase Ib trial of neoadjuvant navtemadlin (previously AMG232 and KRT232) concurrent with preoperative radiotherapy in wild-type p53 soft tissue sarcoma of the extremity and body wall.
Authors: Meng Xu Welliver, Pedro A. Torres-Saavedra, Brian Andrew Van Tine, David G. Kirsch, Michelle A. Rudek, Paul Wakely, Gary K. Schwartz, Raphael E. Pollock, John Michael Kane, Steve B. Jiang, Alan D. Rogers, Peter Houghton, Marta Batus, Andrea Lea Johnston, Matthew Spraker, Krisha Howell, Jonathan Harris, Dian Wang
Journal: Journal of Clinical Oncology (2022)

11521 Background: NRG-DT001 is a phase Ib trial evaluating neoadjuvant navtemadlin with preoperative radiation therapy (RT) in patients (pts) with wild-type (WT) p53 soft tissue sarcoma (STS). The primary objective is to evaluate the safety and tolerability of the MDM2 inhibitor navtemadlin in combination with standard-dose RT in STS in two cohorts (A, extremity or body wall; B, abdomen/pelvis/retroperitoneum) to determine the maximum tolerated dose/recommended phase II dose (MTD/RP2D) of navtemadlin in combination with RT. This report contains the results for cohort A. Methods: Eligible pts had grade 2-3 STS ≥ 5 cm, age ≥ 18, and Zubrod performance status 0-1. Dose levels were 120 mg 2x/week (DL-1), 120 mg 3x/week (DL1), 4x/week (DL2), and 5x/week (DL3) 1 week prior to and during RT (50Gy/5 weeks). Surgery was 5-8 weeks after RT. A 3+3 design was used to make dose escalation/de-escalation decisions at each dose level. Five additional pts were enrolled to the MTD to ensure safety (expansion cohort) with a dose limiting toxicity (DLT) rate of ≤ 1/5 considered safe. The DLT observation period was from the start of navtemadlin until 4 weeks after completion of drug+RT. Tumor Tp53 mutation status was determined by NGS sequencing. All eligible and treated p53 WT pts who experienced DLT or completed the observation period were considered DLT-evaluable. DLT included all grade 4-5 AE definitely, probably, or possibly related to navtemadlin. Any grade 3 AE definitely, probably, or possibly related to navtemadlin was also considered DLT if any of the 2 following situations occurred: a delay of treatment &gt; 2 weeks or ≥ 2 dose reductions due to the grade 3 AE. The decision to escalate or de-escalate was made by consensus of the study team in accordance with the protocol. Results: Between 11/3/2017 and 9/10/2021, 4 (3 WT), 7 (4 WT) and 7 (4 WT) pts were enrolled at DL1, DL2, and DL3 respectively. An additional 9 (5 WT) pts were enrolled on DL3 expansion cohort. Preoperative RT was completed for all except 1 pt (pt refusal/DL3). On DL1 and DL2, 100% of pts completed navtemadlin. On DL3 (including expansion cohort), 78% (7/9) completed navtemadlin (1 AE, 1 pt refusal). On DL1, DL2, and DL3, 3/3, 3/4 (1 disease progression), and 5/6 (1 consent withdrawal; 3 pending) completed surgery. There were no DLTs in any dose level (DL1 0/3, DL2 0/4, DL3 0/9), establishing DL3 as the MTD/RP2D. Tumor necrosis rates will be reported at the time of presentation. Conclusions: Neoadjuvant navtemadlin concurrent with standard dose preoperative RT is well tolerated in patients with WT p53 STS at extremity or body wall, and the 120 mg PO daily of navtemadlin, 5 days per week dose should be used to design future trials of RT with extremity STS. Incorporating NGS sequencing results as an integral biomarker in a clinical trial of neoadjuvant radiotherapy and a radiosensitizer is feasible. Clinical trial information: NRG-DT001 NCT03217266.